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C-reactive protein, procalcitonin and interleukin-6 kinetics in pediatric postoperative patients
Journal of Critical Care 41 (2017) 119–123
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C-reactive protein, procalcitonin and interleukin-6 kinetics in pediatric postoperative patients☆ Andrea Sariego-Jamardo a,⁎, Corsino Rey b,c, Alberto Medina c, Juan Mayordomo-Colunga c, Andrés Concha-Torre c, Belén Prieto d, Ana Vivanco-Allende c a
Paediatric Department, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain University of Oviedo, Oviedo, Spain Pediatric Intensive Care Unit, Hospital Universitario Central de Asturias, Oviedo, Spain d Department of Biochemistry, Hospital Universitario Central de Asturias, Oviedo, Spain b c
1. Introduction Some postoperative pediatric patients require admission to Pediatric Intensive Care Unit (PICU) [1]. Systemic Inflammatory Response Syndrome (SIRS) occurs after surgery in N 80% of patients [2] and makes infection diagnosis difficult by clinical criteria [3]. Biomarkers, such as Creactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) are employed in clinical practice to help in the diagnosis of infectious complications in the postoperative period. CRP, PCT and IL-6 are inflammation markers, so their elevation is secondary to a SIRS due to an infectious or non-infectious cause such as a surgical intervention. The knowledge of the kinetic biomarkers after surgery is important for the postoperative patient management. It has been described that IL-6 reaches its peak value quicker than (2– 3 h) than PCT (6–12 h) or CRP (36–48 h) after surgical intervention. Subsequent decline to baseline values is faster for IL-6, followed by PCT and then CRP [4,5]. Besides, kinetic biomarkers differ depending on the type of surgery [6,7]. Controversy exists over which biomarker has better diagnosis accuracy to characterize infection in postoperative period. There are studies that support PCT usefulness as prognostic marker and diagnostic tool for infection diagnosis during this period [8-19]. Nevertheless, there are other studies that conclude that CRP [20-23] or IL-6 [18,21,24,25] are valid or better for this purpose than PCT. However, the majority of those studies were conducted in children or adults after cardiac surgery and cardiopulmonary bypass [8-10,12,25]. We designed a prospective observational study to evaluate the kinetics of CRP, PCT and IL-6 after different types of surgery in children
Abbreviations: PICU, Pediatric Intensive Care Unit; SIRS, Systemic Inflammatory Response Syndrome; CRP, C-reactive protein; PCT, procalcitonin; IL-6, interleukin-6; ENT surgery, Ear, Nose and Throat surgery; ClS, clean surgery; ClCoS, clean-contaminated surgery; CoS, contaminated surgery; DS, dirty or infected surgery. ☆ Grant numor funding information: Supported in pa/or funding information: Supported in part by a grant of “Fundación Ernesto Sánchez Villares” (01/2012). ⁎ Corresponding author at: Consultas Externas de Neuropediatría, Hospital Universitario Marqués de Valdecilla, Marqués de Valdecilla s/n, 39008 Santander, Spain. E-mail addresses: [email protected] (A. Sariego-Jamardo), [email protected] (C. Rey).
http://dx.doi.org/10.1016/j.jcrc.2017.05.009 0883-9441/© 2017 Elsevier Inc. All rights reserved.
and compare them regarding the proportion of patients with biomarker increase above the cutoff level suggested for diagnosis of sepsis. 2. Materials and methods 2.1. Patient characteristics We conducted a prospective observational study set in an eight-bed PICU of a University Hospital from October 2011 to April 2014. We included all consecutive postoperative patients with informed consent. A total of 123 children were included. Eight patients who suffered from infectious complications in postoperative period were excluded. CRP, PCT and IL-6 levels at 0, 24, 48 and 72 h of postoperative period were analyzed. Patient's epidemiological and clinical data were also collected. The study protocol was approved by the Hospital Ethics Committee of Hospital Universitario Central de Asturias. Written informed consent was obtained from the patient's parents or guardians. 2.2. Classification of surgical procedures Children were classified in different subgroups according to the type of surgical procedure: abdominal surgery, thoracic surgery, Ear, Nose and Throat (ENT) surgery, neurosurgery and orthopedic surgery. Patients were also classified in the four classes of surgical wound types based on degree of bacterial contamination of surgical wounds and risk of infection established by American College of Surgeons [26,27]: class I: clean surgery (ClS), class II clean-contaminated surgery (ClCoS), class III: contaminated surgery (CoS) and class IV: dirty or infected surgery (DS). 2.3. Interpretation of biomarker values Previous published CRP and PCT cutoff values for sepsis in a study performed at our PICU were considered as reference values (CRP: 5.65 mg/dl, PCT: 1.16 ng/ml) [28]. There is less clinical knowledge about the usefulness of IL-6 in sepsis or infection diagnosis and there is a disagreement between the cutoff values established by different authors (ranging from 50 pg/ml to N 200 pg/ml) [4,29-32]. We have chosen 100 pg/ml as a reference cutoff value for sepsis. Proportion of
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samples with biomarker levels above the suggested cutoff values for sepsis were compared between CRP, PCT and IL-6. 2.4. Measurement of PCT, CRP and IL-6 Blood samples were drawn into tubes containing lithium-heparin as anticoagulant, for determination of CRP, PCT and IL-6. Plasma CRP was measured on a Modular Analytics Cobas 6000 (Roche diagnostics, Indianapolis, IN, USA) by an immunoturbidimetric technique. Roche's electro-chemiluminescence immunoassay (ECLIA) was performed on a Cobas 6000 analyzer (e601 module) for measuring PCT and IL-6. Analytical detection limits were 0.07 mg/dl for CRP, 0.02 ng/dl for PCT and 1.5 pg/ml for IL-6. 2.5. Statistical analysis Patient's clinical data and values of plasma biomarkers (CRP, PCT and IL-6) during postoperative period were described using frequencies, percentages, means and medians. CRP, PCT and IL-6 maximal median peak values in postoperative period were analyzed by using Kruskal-Wallis test (non-parametric test), because they do not follow the normality and homoscedasticity hypothesis. The post hoc test of Nemeyi was used when significant differences were found. The percentage of samples that rose above cutoff values for sepsis for each biomarker was analyzed. These percentages were compared between the different surgical subgroups by using Fisher test, and between the different biomarkers by using McNemar test. The level of significance was set at p b 0.05. 3. Results 3.1. Patient characteristics A total of 115 patients were included in the study. Patient characteristics, severity scores, respiratory and inotropic support, red cell transfusions and type of surgery are shown in Table 1. In the abdominal group the most frequent surgical interventions were appendectomy (9 patients; 28.1%) and intestinal anastomosis/ Table 1 Patient characteristics, severity scores, respiratory and inotropic support, red cell transfusions and type of surgery. Results are presented as mean (95% Confidence Interval) for age, weight, number of days in PICU and absolute frequencies and percentages for the rest. TISS-28 = Therapeutic Intervention Scoring System 28; PRISM III = Pediatric Risk of Mortality Score III.
resection (8 patients; 25.0%); thoracoscopic drainage for empyema (12 patients; 36.3%) was the most frequent in thoracic surgery; scoliosis surgery (8 patients; 88.8%) in orthopedic surgery and brain tumor resection (10 patients; 47.6%) in neurosurgery subgroup. In the ENT surgery group there was many surgical procedures (e.g. tonsillectomy 3/ 16 patients, 18.8%; abscess drainage 3/16 patients, 18.8%; cochlear implant placement 2/16 patients, 12.5%; cholesteatoma surgery 1/16 patients, 6.3%) with no predominance between them. The most frequent surgical procedure in ClS was brain tumor neurosurgery (10 patients; 27.7%), while in the case of DS the most frequent surgical procedure was thoracoscopic drainage for empyema (12; 36.3%) followed by appendectomy (9; 27.3%). In the ClCoS group the most common surgical procedure was scoliosis surgery (8/31; 25.8%) and intestinal anastomosis/resection (7/15; 46.7%) in CoS subgroup. The most common perioperative antibiotic prophylaxis in our patients consisted of three doses of cefazolin (33.9% of the patients, mainly from neurosurgery and ENT groups). DS patients received antibiotic treatment according to the type and localization of infection (e.g. empyema, appendectomy). 3.2. CRP kinetics in non-complicated postoperative period after different types of surgery CRP peak level was reached at 48 h after all types of surgery except for orthopedic and ENT surgery (peak value at 72 h) and ClS (peak value at 24 h). CRP median peak values are shown in Table 2. There were differences between the types of surgery (p = 0.04) with neurosurgery vs abdominal surgery close to the level of significance (p = 0.06). In all cases except for ClS, CRP peak median values were elevated above cutoff value for sepsis in postoperative period (Fig. 1). Percentages of samples with CRP levels above cutoff values for sepsis diagnosis are shown in Table 3. There were differences between ClS compared to ClCoS and DS, p b 0.001. 3.3. PCT kinetics in non-complicated postoperative period after different types of surgery PCT peak level was reached at 24 h after all types of surgery except for ENT surgery and orthopedic surgery (peak value at 48 h). PCT median peak values are shown in Table 2 and Fig. 2. There were differences between the types of surgery: p b 0.001, specifically between neurosurgery and abdominal surgery p = 0.02; abdominal and orthopedic
Epidemiological data Age at admission (years) Number of days in PICU Weight (kg) Male sex (%) PRISM III (absolute value) TISS-28 at 24 h (absolute value) TISS-28 at 48 h (absolute value) TISS-28 at 72 h (absolute value) Mechanical ventilation Non-invasive ventilation Inotropic support Red cell transfusion
7.10 (6.15–8.05) 4.29 (2.73–5.85) 27.95 (24.32–31.58) 54.90 1.39 (0.83–1.95) 19.46 (17.67–21.25) 15.95 (14.37–17.53) 15.68 (13.64–17.72) 39 (33.9%) 32 (27.8%) 3 (2.6%) 21 (18.2%)
Type of surgery Abdominal surgery Thoracic surgery ENT (Ear, Nose & Throat) surgery Neurosurgery Orthopedic surgery Other types of surgery Clean surgery Clean-contaminated surgery Contaminated surgery Dirty surgery
32 (27.8%) 33 (28.7%) 16 (13.9%) 21 (18.3%) 9 (7.8%) 4 (3.5%) 36 (31.3%) 31 (27.0%) 15 (13.0%) 33 (28.7%)
Table 2 CRP (mg/dl), PCT (ng/ml) and IL-6 (pg/ml) median of maximal peak values, standard deviation (in brackets) and percentiles 10/90 (below) depending on the type of surgery.
Type of surgical procedure Abdominal surgery Thoracic surgery ENT (Ear, Nose & Throat) surgery Neurosurgery Orthopedic surgery
CRPa
PCTb
IL-6c
13.10 (11.75) 1.88/25.20 7.04 (9.81) 2.02/34.51 1.40 (5.80) 0.21/11.50 4.44 (4.41) 0.05/10.61 6.60 (6.09) 2.60/10.60
1.12 (8.39) 0.26/13.29 0.26 (0.67) 0.14/10.24 0.08 (0.23) 0.03/0.40 0.14 (0.12) 0.06/0.21 0.11 (0.21) 0.07/0.41
173.0 (846.7) 20.50/3696.00 131.0 (111.2) 14.00/309.00 20.0 (22.2) 6.00/67.00 35.0 (338.5) 5.00/51.00 81.0 (57.3) 22.00/162.00
a Kruskal-Wallis for differences between the types of surgery: p = 0.04. Nemenyi post hoc: neurosurgery vs abdominal surgery p = 0.06. b Kruskal-Wallis for differences between the types of surgery: p b 0.001. Nemenyi post hoc: neurosurgery vs abdominal surgery p = 0.02; abdominal vs orthopedic surgery p = 0.03; abdominal vs ENT surgery p = 0.002; abdominal vs thoracic surgery p = 0.017. c Kruskal-Wallis for differences between the types of surgery: p b 0.001. Nemenyi post hoc: neurosurgery vs abdominal surgery p = 0.036; abdominal vs ENT surgery p b 0.001; ENT vs thoracic surgery p = 0.003.
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Fig. 1. CRP (C-reactive protein) kinetics. CRP median values after different types of surgery expressed in mg/dl. Black arrow indicates CRP cutoff in the diagnosis of sepsis (5.65 mg/dl).
surgery p = 0.03; abdominal and ENT surgery p = 0.002 and abdominal and thoracic surgery p = 0.017. Percentages of samples with PCT levels above cutoff values for sepsis diagnosis are shown in Table 3. The percentage of samples elevated above the cutoff of sepsis was higher for abdominal surgery than for the other surgeries (p b 0.001). There were differences between ClS compared to CoS and DS, p b 0.001. 3.4. IL-6 kinetics in non-complicated postoperative period after different types of surgery IL-6 peak level was reached at 0 h after all types of surgery except for abdominal surgery and ClS (peak value at 24 h). IL-6 median peak values are shown in Table 2 and Fig. 3. IL-6 median values were below the cutoff values for sepsis after all types of surgery, except DS, abdominal surgery and thoracic surgery. There were differences between the types of surgery: p b 0.001, specifically, neurosurgery vs abdominal surgery p = 0.036; abdominal vs ENT surgery p b 0.001; and, ENT vs thoracic surgery p = 0.003. Percentages of samples with IL-6 levels above cutoff values for sepsis diagnosis are shown in Table 3. The percentage of samples elevated above the cutoff values for sepsis was higher for abdominal and thoracic surgery than for the other surgeries (p b 0.001). There were differences between ClS compared to the other three types of surgery, p b 0.01. 3.5. Biomarker comparison Comparison of the biomarkers percentage of elevation above cutoff value for sepsis is shown in Table 3. There were no differences in case of abdominal surgery, neurosurgery and CoS. In thoracic surgery, ClS and ClCoS, PCT percentage was lower than CRP and IL-6 (p b 0.05). In ENT and DS, PCT and IL-6 percentages were lower than CRP (p b 0.05). Finally, in orthopedic surgery PCT percentage was lower than CRP (p b 0.05). 4. Discussion Our data confirmed that kinetic biomarkers after different types of surgery vary according to the type of biomarker and the type of surgery. We also found differences between the biomarkers in the percentage of cases with values above the cutoff for sepsis. Maximal peak of elevation for PCT and IL-6 occurred earlier (in the first 24 h of postoperative period) than for CRP (at 48–72 h after surgery). These results support previous findings about postoperative kinetic biomarker [6,7,10,12,17,20,23,24,33-35]. Maximal peak of PCT
occurred later (at 48 h) in MacMaster et al. and Michalik et al. studies that included pediatric patients after cardiothoracic surgery [8,9]. We did not include patients undergoing cardiothoracic surgery, thus the data are not comparable. However, in our group of ENT patients, peak level of PCT occurred at 48 h supporting that in some types of surgery the kinetic could be slower. We found differences related to PCT and IL-6 increase depending on the type of surgery. Both biomarkers were more elevated after abdominal surgery than after other types of surgery, probably due to the high percentage of patients with DS in abdominal surgery. On the other hand, CRP increased in a very high percentage of patients without differences according to the type of surgery. Our data supports Meisner et al. [6,7] results, with differences in PCT values according to the type of surgery and CRP increase in almost all patients without differences according to the type of surgery. In the case of Pavcnik study almost all the patients underwent abdominal surgery [7].
Table 3 Percentages of samples with biomarker levels above their respective cutoff values for sepsis diagnosis (5.65 mg/dl for C-Reactive Protein, 1.16 ng/ml for Procalcitonin and 100 pg/ml for Interleukin-6), depending on the type of surgery. The percentages of samples above cutoff values for sepsis were compared between the different surgical subgroups by using Fisher test and between biomarkers by using McNemar test. Differences were found between the following subgroups: 1. p b 0.001 compared to thoracic, ENT, neurosurgery and orthopedic surgery 2. p b 0.001 compared to ENT, neurosurgery and orthopedic surgery 3. p b 0.001 compared to ClCoS and DS 4. p b 0.001 compared to CoS and DS. 5. p b 0,01 compared to ClCoS, CoS and DS. Differences were found between the following biomarkers: a. p b 0.005 compared to CRP and IL-6. b. p b 0.05 compared to PCT and IL-6. c. p b 0.05 compared to PCT. d. p b 0.05 compared to CRP and IL-6.
Type of surgical procedure Abdominal surgery Thoracic surgery ENT (Ear, Nose & Throat) surgery Neurosurgery Orthopedic surgery
CRP
PCT
IL-6
65.22% 60.87% 40.00%b 28.57% 66.67%c
47.83%1 17.39%a 0.00% 0.00% 0.00%
65.22%2 60.87%2 0.00% 21.43% 33.33%
Types of surgery according to the American college of surgeons surgical classification 0.00%d,4 18.18%5 Clean surgery (ClS) 18.18%3 Clean-contaminated surgery (ClCoS) 57.69% 3.85%d 42.31% Contaminated surgery (CoS) 27.27% 18.18% 36.36% 52.17% 69.57% Dirty surgery (DS) 95.65%b
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Fig. 2. PCT (Procalcitonin) kinetics. PCT median values after different types of surgery expressed in ng/ml. Black arrow indicates PCT cutoff in the diagnosis of sepsis (1.16 ng/ml).
We also divided the patients according to the surgical classification from the American College of Surgeons [26,27]. To the best of our knowledge, the patients were not classified systematically depending on the degree of contamination of surgical wounds in previous studies. CRP, PCT and IL-6 values were more elevated after DS than after the other types of surgery. As we have explained before the majority of procedures classified as CoS were abdominal surgical procedures. It is well known that during abdominal surgery, bacterial endotoxins are liberated. Bacterial endotoxin injection was correlated with an elevation in PCT levels in previous studies [36]. We propose to employ the classification established by the American College of Surgeons [26,27] for a best interpretation of kinetic biomarkers and in order to standardize the results in further studies. Elevation above cutoff for sepsis occurred in a larger percentage of cases for CRP than for PCT and IL-6 in all types of surgery, except abdominal and neurosurgery. For the clinical practice it is important to consider that PCT did not increase above cutoff for sepsis in any case of ENT surgery, neurosurgery, orthopedic surgery. IL-6 did not increase in any case of ENT surgery (Table 3). The elevation above the cutoff for sepsis occurs in a larger percentage of cases after DS for the three biomarkers, especially for CRP. An important finding is that after ClS, PCT was not elevated above sepsis cutoff values whereas CRP and IL-6 were elevated in 18% of the cases. These data are similar to those observed by Meisner et al. [6].
Our data support that PCT and IL-6 seem to be better biomarkers in postoperative period than CRP. PCT is especially useful in ClS and ClCoS. Previous studies, in which PCT was also considered a better marker of infectious complications in postoperative period [6,8,13,15-18,22,25, 33,34], agree with our results. However, in the studies conducted by Pavcnik et al. [7] and Neunhoeffer et al. [24], IL-8 and IL-6 were considered better markers of infection in postoperative period. This may be explained by the fact that newborns were included in these studies. It is well known that a physiological elevation of PCT in the early neonatal period can interfere with the diagnosis of infection [37]. Our study has limitations. First, we have performed an observational study that does not allow to draw any conclusion concerning therapy and outcome results. Second, our PICU cannot be considered as representative of all PICUs around the world. Kinetic Biomarkers could be different if the population was different. However, our results agree with previous studies performed in other countries. Third, some subgroups of the sample (for example, orthopedic surgery) include a small number of patients making statistical comparisons difficult. Early diagnosis and treatment of nosocomial sepsis influences patient's prognosis. An important limitation of CRP, PCT and IL-6 is that their levels rise in the presence of any inflammatory response, both when the cause is infection and when it is tissue injury (for example after a surgical intervention). Therefore when we have an elevated
Fig. 3. IL-6 (interleukin 6) kinetics. IL-6 median values after different types of surgery expressed in pg/ml. Black arrow indicates IL-6 cutoff in the diagnosis of sepsis (100 pg/ml).
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result, we have to decide whether the surgery explains the increase or whether, on the contrary, we should begin antibiotic treatment immediately [38]. Our results can be useful in clinical practice, highlighting that biomarker elevations (especially PCT) above cut-off value for sepsis in the postoperative period of ClS, ClCoS, ENT, neurosurgery and orthopedic surgery are very suggestive of nosocomial sepsis. Therefore, sepsis diagnosis and antibiotic treatment should be started immediately. On the other hand, biomarker elevations in the postoperative period of DS are less useful for the diagnosis of nosocomial sepsis. Our results contribute to increase the knowledge of CRP, PCT and IL6 kinetics in non complicated postoperative period depending on the type of surgery. This knowledge is important in clinical practice to help in the approach to nosocomial sepsis [21,39]. 5. Conclusions Postoperative SIRS leads to an elevation in CRP, PCT and IL-6, that is different depending on the type of surgery and the biomarker. Biomarker elevations are higher after abdominal surgery and DS. PCT showed an early peak at 24 h after surgery with a rapid decrease. PCT showed no significant increase after ClS and ClCoS. Therefore, PCT increase after 24 h of postoperative period has clinical impact whereas the course of CRP and IL-6 remains unclear for clinical use. PCT seems to be a more useful tool than CRP or IL-6 to guide diagnosis and antibiotic approach of nosocomial sepsis in the postoperative period. Conflict of interest to disclosure Corsino Rey had received speaker honoraria from Brahms and Thermofisher Companies to attend meetings related to sepsis biomarkers. The rest of the authors declare no conflicts of interest. Acknowledgments and credits The authors gratefully acknowledge the assistance of the medical, nursing and technical staff from PICU and Laboratory of Hospital Universitario Central de Asturias. References [1] Garcia S, Ruza F, Alvarado F, Madero R, Delgado MA, Dorao P, et al. Analysis of costs in a pediatric ICU. Intensive Care Med 1997;23(2):218–25. [2] Brun-Buisson C. The epidemiology of the systemic inflammatory response. Intensive Care Med 2000;26(Suppl. 1):S64–74. [3] Karzai W, Reinhart K. Sepsis: definitions and diagnosis. Int J Clin Pract Suppl 1998; 95:44–8. [4] Lacour AG, Gervaix A, Zamora SA, Vadas L, Lombard PR, Dayer JM, et al. Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identificators of serious bacterial infections in children with fever without localising signs. Eur J Pediatr 2001;160(2):95–100. [5] Brunkhorst FM, Heinz U, Forycki ZF. Kinetics of procalcitonin in iatrogenic sepsis. Intensive Care Med 1998;24(8):888–9. [6] Meisner M, Tschaikowsky K, Hutzler A, Schick C, Schuttler J. Postoperative plasma concentrations of procalcitonin after different types of surgery. Intensive Care Med 1998;24(7):680–4. [7] Pavcnik-Arnol M, Bonac B, Groselj-Grenc M, Derganc M. Changes in serum procalcitonin, interleukin 6, interleukin 8 and C-reactive protein in neonates after surgery. Eur J Pediatr Surg 2010;20(4):262–6. [8] McMaster P, Park DY, Shann F, Cochrane A, Morris K, Gray J, et al. Procalcitonin versus C-reactive protein and immature-to-total neutrophil ratio as markers of infection after cardiopulmonary bypass in children. Pediatr Crit Care Med 2009;10(2): 217–21. [9] Michalik DE, Duncan BW, Mee RB, Worley S, Goldfarb J, Danziger-Isakov LA, et al. Quantitative analysis of procalcitonin after pediatric cardiothoracic surgery. Cardiol Young 2006;16(1):48–53. [10] Celebi S, Koner O, Menda F, Balci H, Hatemi A, Korkut K, et al. Procalcitonin kinetics in pediatric patients with systemic inflammatory response after open heart surgery. Intensive Care Med 2006;32(6):881–7. [11] Arkader R, Troster EJ, Lopes MR, Junior RR, Carcillo JA, Leone C, et al. Procalcitonin does discriminate between sepsis and systemic inflammatory response syndrome. Arch Dis Child 2006;91(2):117–20. [12] Jebali MA, Hausfater P, Abbes Z, Aouni Z, Riou B, Ferjani M. Assessment of the accuracy of procalcitonin to diagnose postoperative infection after cardiac surgery. Anesthesiology 2007;107(2):232–8.
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C-reactive protein, procalcitonin and interleukin-6 kinetics in pediatric postoperative patients☆ Andrea Sariego-Jamardo a,⁎, Corsino Rey b,c, Alberto Medina c, Juan Mayordomo-Colunga c, Andrés Concha-Torre c, Belén Prieto d, Ana Vivanco-Allende c a
Paediatric Department, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain University of Oviedo, Oviedo, Spain Pediatric Intensive Care Unit, Hospital Universitario Central de Asturias, Oviedo, Spain d Department of Biochemistry, Hospital Universitario Central de Asturias, Oviedo, Spain b c
1. Introduction Some postoperative pediatric patients require admission to Pediatric Intensive Care Unit (PICU) [1]. Systemic Inflammatory Response Syndrome (SIRS) occurs after surgery in N 80% of patients [2] and makes infection diagnosis difficult by clinical criteria [3]. Biomarkers, such as Creactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) are employed in clinical practice to help in the diagnosis of infectious complications in the postoperative period. CRP, PCT and IL-6 are inflammation markers, so their elevation is secondary to a SIRS due to an infectious or non-infectious cause such as a surgical intervention. The knowledge of the kinetic biomarkers after surgery is important for the postoperative patient management. It has been described that IL-6 reaches its peak value quicker than (2– 3 h) than PCT (6–12 h) or CRP (36–48 h) after surgical intervention. Subsequent decline to baseline values is faster for IL-6, followed by PCT and then CRP [4,5]. Besides, kinetic biomarkers differ depending on the type of surgery [6,7]. Controversy exists over which biomarker has better diagnosis accuracy to characterize infection in postoperative period. There are studies that support PCT usefulness as prognostic marker and diagnostic tool for infection diagnosis during this period [8-19]. Nevertheless, there are other studies that conclude that CRP [20-23] or IL-6 [18,21,24,25] are valid or better for this purpose than PCT. However, the majority of those studies were conducted in children or adults after cardiac surgery and cardiopulmonary bypass [8-10,12,25]. We designed a prospective observational study to evaluate the kinetics of CRP, PCT and IL-6 after different types of surgery in children
Abbreviations: PICU, Pediatric Intensive Care Unit; SIRS, Systemic Inflammatory Response Syndrome; CRP, C-reactive protein; PCT, procalcitonin; IL-6, interleukin-6; ENT surgery, Ear, Nose and Throat surgery; ClS, clean surgery; ClCoS, clean-contaminated surgery; CoS, contaminated surgery; DS, dirty or infected surgery. ☆ Grant numor funding information: Supported in pa/or funding information: Supported in part by a grant of “Fundación Ernesto Sánchez Villares” (01/2012). ⁎ Corresponding author at: Consultas Externas de Neuropediatría, Hospital Universitario Marqués de Valdecilla, Marqués de Valdecilla s/n, 39008 Santander, Spain. E-mail addresses: [email protected] (A. Sariego-Jamardo), [email protected] (C. Rey).
http://dx.doi.org/10.1016/j.jcrc.2017.05.009 0883-9441/© 2017 Elsevier Inc. All rights reserved.
and compare them regarding the proportion of patients with biomarker increase above the cutoff level suggested for diagnosis of sepsis. 2. Materials and methods 2.1. Patient characteristics We conducted a prospective observational study set in an eight-bed PICU of a University Hospital from October 2011 to April 2014. We included all consecutive postoperative patients with informed consent. A total of 123 children were included. Eight patients who suffered from infectious complications in postoperative period were excluded. CRP, PCT and IL-6 levels at 0, 24, 48 and 72 h of postoperative period were analyzed. Patient's epidemiological and clinical data were also collected. The study protocol was approved by the Hospital Ethics Committee of Hospital Universitario Central de Asturias. Written informed consent was obtained from the patient's parents or guardians. 2.2. Classification of surgical procedures Children were classified in different subgroups according to the type of surgical procedure: abdominal surgery, thoracic surgery, Ear, Nose and Throat (ENT) surgery, neurosurgery and orthopedic surgery. Patients were also classified in the four classes of surgical wound types based on degree of bacterial contamination of surgical wounds and risk of infection established by American College of Surgeons [26,27]: class I: clean surgery (ClS), class II clean-contaminated surgery (ClCoS), class III: contaminated surgery (CoS) and class IV: dirty or infected surgery (DS). 2.3. Interpretation of biomarker values Previous published CRP and PCT cutoff values for sepsis in a study performed at our PICU were considered as reference values (CRP: 5.65 mg/dl, PCT: 1.16 ng/ml) [28]. There is less clinical knowledge about the usefulness of IL-6 in sepsis or infection diagnosis and there is a disagreement between the cutoff values established by different authors (ranging from 50 pg/ml to N 200 pg/ml) [4,29-32]. We have chosen 100 pg/ml as a reference cutoff value for sepsis. Proportion of
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samples with biomarker levels above the suggested cutoff values for sepsis were compared between CRP, PCT and IL-6. 2.4. Measurement of PCT, CRP and IL-6 Blood samples were drawn into tubes containing lithium-heparin as anticoagulant, for determination of CRP, PCT and IL-6. Plasma CRP was measured on a Modular Analytics Cobas 6000 (Roche diagnostics, Indianapolis, IN, USA) by an immunoturbidimetric technique. Roche's electro-chemiluminescence immunoassay (ECLIA) was performed on a Cobas 6000 analyzer (e601 module) for measuring PCT and IL-6. Analytical detection limits were 0.07 mg/dl for CRP, 0.02 ng/dl for PCT and 1.5 pg/ml for IL-6. 2.5. Statistical analysis Patient's clinical data and values of plasma biomarkers (CRP, PCT and IL-6) during postoperative period were described using frequencies, percentages, means and medians. CRP, PCT and IL-6 maximal median peak values in postoperative period were analyzed by using Kruskal-Wallis test (non-parametric test), because they do not follow the normality and homoscedasticity hypothesis. The post hoc test of Nemeyi was used when significant differences were found. The percentage of samples that rose above cutoff values for sepsis for each biomarker was analyzed. These percentages were compared between the different surgical subgroups by using Fisher test, and between the different biomarkers by using McNemar test. The level of significance was set at p b 0.05. 3. Results 3.1. Patient characteristics A total of 115 patients were included in the study. Patient characteristics, severity scores, respiratory and inotropic support, red cell transfusions and type of surgery are shown in Table 1. In the abdominal group the most frequent surgical interventions were appendectomy (9 patients; 28.1%) and intestinal anastomosis/ Table 1 Patient characteristics, severity scores, respiratory and inotropic support, red cell transfusions and type of surgery. Results are presented as mean (95% Confidence Interval) for age, weight, number of days in PICU and absolute frequencies and percentages for the rest. TISS-28 = Therapeutic Intervention Scoring System 28; PRISM III = Pediatric Risk of Mortality Score III.
resection (8 patients; 25.0%); thoracoscopic drainage for empyema (12 patients; 36.3%) was the most frequent in thoracic surgery; scoliosis surgery (8 patients; 88.8%) in orthopedic surgery and brain tumor resection (10 patients; 47.6%) in neurosurgery subgroup. In the ENT surgery group there was many surgical procedures (e.g. tonsillectomy 3/ 16 patients, 18.8%; abscess drainage 3/16 patients, 18.8%; cochlear implant placement 2/16 patients, 12.5%; cholesteatoma surgery 1/16 patients, 6.3%) with no predominance between them. The most frequent surgical procedure in ClS was brain tumor neurosurgery (10 patients; 27.7%), while in the case of DS the most frequent surgical procedure was thoracoscopic drainage for empyema (12; 36.3%) followed by appendectomy (9; 27.3%). In the ClCoS group the most common surgical procedure was scoliosis surgery (8/31; 25.8%) and intestinal anastomosis/resection (7/15; 46.7%) in CoS subgroup. The most common perioperative antibiotic prophylaxis in our patients consisted of three doses of cefazolin (33.9% of the patients, mainly from neurosurgery and ENT groups). DS patients received antibiotic treatment according to the type and localization of infection (e.g. empyema, appendectomy). 3.2. CRP kinetics in non-complicated postoperative period after different types of surgery CRP peak level was reached at 48 h after all types of surgery except for orthopedic and ENT surgery (peak value at 72 h) and ClS (peak value at 24 h). CRP median peak values are shown in Table 2. There were differences between the types of surgery (p = 0.04) with neurosurgery vs abdominal surgery close to the level of significance (p = 0.06). In all cases except for ClS, CRP peak median values were elevated above cutoff value for sepsis in postoperative period (Fig. 1). Percentages of samples with CRP levels above cutoff values for sepsis diagnosis are shown in Table 3. There were differences between ClS compared to ClCoS and DS, p b 0.001. 3.3. PCT kinetics in non-complicated postoperative period after different types of surgery PCT peak level was reached at 24 h after all types of surgery except for ENT surgery and orthopedic surgery (peak value at 48 h). PCT median peak values are shown in Table 2 and Fig. 2. There were differences between the types of surgery: p b 0.001, specifically between neurosurgery and abdominal surgery p = 0.02; abdominal and orthopedic
Epidemiological data Age at admission (years) Number of days in PICU Weight (kg) Male sex (%) PRISM III (absolute value) TISS-28 at 24 h (absolute value) TISS-28 at 48 h (absolute value) TISS-28 at 72 h (absolute value) Mechanical ventilation Non-invasive ventilation Inotropic support Red cell transfusion
7.10 (6.15–8.05) 4.29 (2.73–5.85) 27.95 (24.32–31.58) 54.90 1.39 (0.83–1.95) 19.46 (17.67–21.25) 15.95 (14.37–17.53) 15.68 (13.64–17.72) 39 (33.9%) 32 (27.8%) 3 (2.6%) 21 (18.2%)
Type of surgery Abdominal surgery Thoracic surgery ENT (Ear, Nose & Throat) surgery Neurosurgery Orthopedic surgery Other types of surgery Clean surgery Clean-contaminated surgery Contaminated surgery Dirty surgery
32 (27.8%) 33 (28.7%) 16 (13.9%) 21 (18.3%) 9 (7.8%) 4 (3.5%) 36 (31.3%) 31 (27.0%) 15 (13.0%) 33 (28.7%)
Table 2 CRP (mg/dl), PCT (ng/ml) and IL-6 (pg/ml) median of maximal peak values, standard deviation (in brackets) and percentiles 10/90 (below) depending on the type of surgery.
Type of surgical procedure Abdominal surgery Thoracic surgery ENT (Ear, Nose & Throat) surgery Neurosurgery Orthopedic surgery
CRPa
PCTb
IL-6c
13.10 (11.75) 1.88/25.20 7.04 (9.81) 2.02/34.51 1.40 (5.80) 0.21/11.50 4.44 (4.41) 0.05/10.61 6.60 (6.09) 2.60/10.60
1.12 (8.39) 0.26/13.29 0.26 (0.67) 0.14/10.24 0.08 (0.23) 0.03/0.40 0.14 (0.12) 0.06/0.21 0.11 (0.21) 0.07/0.41
173.0 (846.7) 20.50/3696.00 131.0 (111.2) 14.00/309.00 20.0 (22.2) 6.00/67.00 35.0 (338.5) 5.00/51.00 81.0 (57.3) 22.00/162.00
a Kruskal-Wallis for differences between the types of surgery: p = 0.04. Nemenyi post hoc: neurosurgery vs abdominal surgery p = 0.06. b Kruskal-Wallis for differences between the types of surgery: p b 0.001. Nemenyi post hoc: neurosurgery vs abdominal surgery p = 0.02; abdominal vs orthopedic surgery p = 0.03; abdominal vs ENT surgery p = 0.002; abdominal vs thoracic surgery p = 0.017. c Kruskal-Wallis for differences between the types of surgery: p b 0.001. Nemenyi post hoc: neurosurgery vs abdominal surgery p = 0.036; abdominal vs ENT surgery p b 0.001; ENT vs thoracic surgery p = 0.003.
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Fig. 1. CRP (C-reactive protein) kinetics. CRP median values after different types of surgery expressed in mg/dl. Black arrow indicates CRP cutoff in the diagnosis of sepsis (5.65 mg/dl).
surgery p = 0.03; abdominal and ENT surgery p = 0.002 and abdominal and thoracic surgery p = 0.017. Percentages of samples with PCT levels above cutoff values for sepsis diagnosis are shown in Table 3. The percentage of samples elevated above the cutoff of sepsis was higher for abdominal surgery than for the other surgeries (p b 0.001). There were differences between ClS compared to CoS and DS, p b 0.001. 3.4. IL-6 kinetics in non-complicated postoperative period after different types of surgery IL-6 peak level was reached at 0 h after all types of surgery except for abdominal surgery and ClS (peak value at 24 h). IL-6 median peak values are shown in Table 2 and Fig. 3. IL-6 median values were below the cutoff values for sepsis after all types of surgery, except DS, abdominal surgery and thoracic surgery. There were differences between the types of surgery: p b 0.001, specifically, neurosurgery vs abdominal surgery p = 0.036; abdominal vs ENT surgery p b 0.001; and, ENT vs thoracic surgery p = 0.003. Percentages of samples with IL-6 levels above cutoff values for sepsis diagnosis are shown in Table 3. The percentage of samples elevated above the cutoff values for sepsis was higher for abdominal and thoracic surgery than for the other surgeries (p b 0.001). There were differences between ClS compared to the other three types of surgery, p b 0.01. 3.5. Biomarker comparison Comparison of the biomarkers percentage of elevation above cutoff value for sepsis is shown in Table 3. There were no differences in case of abdominal surgery, neurosurgery and CoS. In thoracic surgery, ClS and ClCoS, PCT percentage was lower than CRP and IL-6 (p b 0.05). In ENT and DS, PCT and IL-6 percentages were lower than CRP (p b 0.05). Finally, in orthopedic surgery PCT percentage was lower than CRP (p b 0.05). 4. Discussion Our data confirmed that kinetic biomarkers after different types of surgery vary according to the type of biomarker and the type of surgery. We also found differences between the biomarkers in the percentage of cases with values above the cutoff for sepsis. Maximal peak of elevation for PCT and IL-6 occurred earlier (in the first 24 h of postoperative period) than for CRP (at 48–72 h after surgery). These results support previous findings about postoperative kinetic biomarker [6,7,10,12,17,20,23,24,33-35]. Maximal peak of PCT
occurred later (at 48 h) in MacMaster et al. and Michalik et al. studies that included pediatric patients after cardiothoracic surgery [8,9]. We did not include patients undergoing cardiothoracic surgery, thus the data are not comparable. However, in our group of ENT patients, peak level of PCT occurred at 48 h supporting that in some types of surgery the kinetic could be slower. We found differences related to PCT and IL-6 increase depending on the type of surgery. Both biomarkers were more elevated after abdominal surgery than after other types of surgery, probably due to the high percentage of patients with DS in abdominal surgery. On the other hand, CRP increased in a very high percentage of patients without differences according to the type of surgery. Our data supports Meisner et al. [6,7] results, with differences in PCT values according to the type of surgery and CRP increase in almost all patients without differences according to the type of surgery. In the case of Pavcnik study almost all the patients underwent abdominal surgery [7].
Table 3 Percentages of samples with biomarker levels above their respective cutoff values for sepsis diagnosis (5.65 mg/dl for C-Reactive Protein, 1.16 ng/ml for Procalcitonin and 100 pg/ml for Interleukin-6), depending on the type of surgery. The percentages of samples above cutoff values for sepsis were compared between the different surgical subgroups by using Fisher test and between biomarkers by using McNemar test. Differences were found between the following subgroups: 1. p b 0.001 compared to thoracic, ENT, neurosurgery and orthopedic surgery 2. p b 0.001 compared to ENT, neurosurgery and orthopedic surgery 3. p b 0.001 compared to ClCoS and DS 4. p b 0.001 compared to CoS and DS. 5. p b 0,01 compared to ClCoS, CoS and DS. Differences were found between the following biomarkers: a. p b 0.005 compared to CRP and IL-6. b. p b 0.05 compared to PCT and IL-6. c. p b 0.05 compared to PCT. d. p b 0.05 compared to CRP and IL-6.
Type of surgical procedure Abdominal surgery Thoracic surgery ENT (Ear, Nose & Throat) surgery Neurosurgery Orthopedic surgery
CRP
PCT
IL-6
65.22% 60.87% 40.00%b 28.57% 66.67%c
47.83%1 17.39%a 0.00% 0.00% 0.00%
65.22%2 60.87%2 0.00% 21.43% 33.33%
Types of surgery according to the American college of surgeons surgical classification 0.00%d,4 18.18%5 Clean surgery (ClS) 18.18%3 Clean-contaminated surgery (ClCoS) 57.69% 3.85%d 42.31% Contaminated surgery (CoS) 27.27% 18.18% 36.36% 52.17% 69.57% Dirty surgery (DS) 95.65%b
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Fig. 2. PCT (Procalcitonin) kinetics. PCT median values after different types of surgery expressed in ng/ml. Black arrow indicates PCT cutoff in the diagnosis of sepsis (1.16 ng/ml).
We also divided the patients according to the surgical classification from the American College of Surgeons [26,27]. To the best of our knowledge, the patients were not classified systematically depending on the degree of contamination of surgical wounds in previous studies. CRP, PCT and IL-6 values were more elevated after DS than after the other types of surgery. As we have explained before the majority of procedures classified as CoS were abdominal surgical procedures. It is well known that during abdominal surgery, bacterial endotoxins are liberated. Bacterial endotoxin injection was correlated with an elevation in PCT levels in previous studies [36]. We propose to employ the classification established by the American College of Surgeons [26,27] for a best interpretation of kinetic biomarkers and in order to standardize the results in further studies. Elevation above cutoff for sepsis occurred in a larger percentage of cases for CRP than for PCT and IL-6 in all types of surgery, except abdominal and neurosurgery. For the clinical practice it is important to consider that PCT did not increase above cutoff for sepsis in any case of ENT surgery, neurosurgery, orthopedic surgery. IL-6 did not increase in any case of ENT surgery (Table 3). The elevation above the cutoff for sepsis occurs in a larger percentage of cases after DS for the three biomarkers, especially for CRP. An important finding is that after ClS, PCT was not elevated above sepsis cutoff values whereas CRP and IL-6 were elevated in 18% of the cases. These data are similar to those observed by Meisner et al. [6].
Our data support that PCT and IL-6 seem to be better biomarkers in postoperative period than CRP. PCT is especially useful in ClS and ClCoS. Previous studies, in which PCT was also considered a better marker of infectious complications in postoperative period [6,8,13,15-18,22,25, 33,34], agree with our results. However, in the studies conducted by Pavcnik et al. [7] and Neunhoeffer et al. [24], IL-8 and IL-6 were considered better markers of infection in postoperative period. This may be explained by the fact that newborns were included in these studies. It is well known that a physiological elevation of PCT in the early neonatal period can interfere with the diagnosis of infection [37]. Our study has limitations. First, we have performed an observational study that does not allow to draw any conclusion concerning therapy and outcome results. Second, our PICU cannot be considered as representative of all PICUs around the world. Kinetic Biomarkers could be different if the population was different. However, our results agree with previous studies performed in other countries. Third, some subgroups of the sample (for example, orthopedic surgery) include a small number of patients making statistical comparisons difficult. Early diagnosis and treatment of nosocomial sepsis influences patient's prognosis. An important limitation of CRP, PCT and IL-6 is that their levels rise in the presence of any inflammatory response, both when the cause is infection and when it is tissue injury (for example after a surgical intervention). Therefore when we have an elevated
Fig. 3. IL-6 (interleukin 6) kinetics. IL-6 median values after different types of surgery expressed in pg/ml. Black arrow indicates IL-6 cutoff in the diagnosis of sepsis (100 pg/ml).
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result, we have to decide whether the surgery explains the increase or whether, on the contrary, we should begin antibiotic treatment immediately [38]. Our results can be useful in clinical practice, highlighting that biomarker elevations (especially PCT) above cut-off value for sepsis in the postoperative period of ClS, ClCoS, ENT, neurosurgery and orthopedic surgery are very suggestive of nosocomial sepsis. Therefore, sepsis diagnosis and antibiotic treatment should be started immediately. On the other hand, biomarker elevations in the postoperative period of DS are less useful for the diagnosis of nosocomial sepsis. Our results contribute to increase the knowledge of CRP, PCT and IL6 kinetics in non complicated postoperative period depending on the type of surgery. This knowledge is important in clinical practice to help in the approach to nosocomial sepsis [21,39]. 5. Conclusions Postoperative SIRS leads to an elevation in CRP, PCT and IL-6, that is different depending on the type of surgery and the biomarker. Biomarker elevations are higher after abdominal surgery and DS. PCT showed an early peak at 24 h after surgery with a rapid decrease. PCT showed no significant increase after ClS and ClCoS. Therefore, PCT increase after 24 h of postoperative period has clinical impact whereas the course of CRP and IL-6 remains unclear for clinical use. PCT seems to be a more useful tool than CRP or IL-6 to guide diagnosis and antibiotic approach of nosocomial sepsis in the postoperative period. Conflict of interest to disclosure Corsino Rey had received speaker honoraria from Brahms and Thermofisher Companies to attend meetings related to sepsis biomarkers. The rest of the authors declare no conflicts of interest. Acknowledgments and credits The authors gratefully acknowledge the assistance of the medical, nursing and technical staff from PICU and Laboratory of Hospital Universitario Central de Asturias. References [1] Garcia S, Ruza F, Alvarado F, Madero R, Delgado MA, Dorao P, et al. Analysis of costs in a pediatric ICU. Intensive Care Med 1997;23(2):218–25. [2] Brun-Buisson C. The epidemiology of the systemic inflammatory response. Intensive Care Med 2000;26(Suppl. 1):S64–74. [3] Karzai W, Reinhart K. Sepsis: definitions and diagnosis. Int J Clin Pract Suppl 1998; 95:44–8. [4] Lacour AG, Gervaix A, Zamora SA, Vadas L, Lombard PR, Dayer JM, et al. Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identificators of serious bacterial infections in children with fever without localising signs. Eur J Pediatr 2001;160(2):95–100. [5] Brunkhorst FM, Heinz U, Forycki ZF. Kinetics of procalcitonin in iatrogenic sepsis. Intensive Care Med 1998;24(8):888–9. [6] Meisner M, Tschaikowsky K, Hutzler A, Schick C, Schuttler J. Postoperative plasma concentrations of procalcitonin after different types of surgery. Intensive Care Med 1998;24(7):680–4. [7] Pavcnik-Arnol M, Bonac B, Groselj-Grenc M, Derganc M. Changes in serum procalcitonin, interleukin 6, interleukin 8 and C-reactive protein in neonates after surgery. Eur J Pediatr Surg 2010;20(4):262–6. [8] McMaster P, Park DY, Shann F, Cochrane A, Morris K, Gray J, et al. Procalcitonin versus C-reactive protein and immature-to-total neutrophil ratio as markers of infection after cardiopulmonary bypass in children. Pediatr Crit Care Med 2009;10(2): 217–21. [9] Michalik DE, Duncan BW, Mee RB, Worley S, Goldfarb J, Danziger-Isakov LA, et al. Quantitative analysis of procalcitonin after pediatric cardiothoracic surgery. Cardiol Young 2006;16(1):48–53. [10] Celebi S, Koner O, Menda F, Balci H, Hatemi A, Korkut K, et al. Procalcitonin kinetics in pediatric patients with systemic inflammatory response after open heart surgery. Intensive Care Med 2006;32(6):881–7. [11] Arkader R, Troster EJ, Lopes MR, Junior RR, Carcillo JA, Leone C, et al. Procalcitonin does discriminate between sepsis and systemic inflammatory response syndrome. Arch Dis Child 2006;91(2):117–20. [12] Jebali MA, Hausfater P, Abbes Z, Aouni Z, Riou B, Ferjani M. Assessment of the accuracy of procalcitonin to diagnose postoperative infection after cardiac surgery. Anesthesiology 2007;107(2):232–8.
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